miRNA 介导的 TUSC3 缺失增强 UPR 和 ERAD，促进 NSCLC 的转移潜能。
miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC.
机构信息
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.
出版信息
Nat Commun. 2018 Nov 30;9(1):5110. doi: 10.1038/s41467-018-07561-8.
Non-small cell lung carcinoma (NSCLC) is leading cause of cancer-related deaths in the world. The Tumor Suppressor Candidate 3 (TUSC3) at chromosome 8p22 known to be frequently deleted in cancer is often found to be deleted in advanced stage of solid tumors. However, the role of TUSC3 still remains controversial in lung cancer and context-dependent in several cancers. Here we propose that miR-224/-520c-dependent TUSC3 deficiency enhances the metastatic potential of NSCLC through the alteration of three unfolded protein response pathways and HRD1-dependent ERAD. ATF6α-dependent UPR is enhanced whereas the affinity of HRD1 to its substrates, PERK, IRE1α and p53 is weakened. Consequently, the alteration of UPRs and the suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is ultimately responsible for enhancing metastatic potential of lung cancer. These findings provide mechanistic insight of unrecognized roles of TUSC3 in cancer progression and the oncogenic role of HRD1-dependent ERAD in cancer metastasis.
非小细胞肺癌（NSCLC）是世界上癌症相关死亡的主要原因。在癌症中经常发现染色体 8p22 上的肿瘤抑制候选基因 3（TUSC3）频繁缺失，并且通常在实体瘤的晚期发现缺失。然而，TUSC3 在肺癌中的作用仍然存在争议，并且在几种癌症中具有上下文依赖性。在这里，我们提出 miR-224/-520c 依赖性 TUSC3 缺乏通过改变三种未折叠蛋白反应途径和 HRD1 依赖性 ERAD 增强 NSCLC 的转移潜力。ATF6α 依赖性 UPR 增强，而 HRD1 与其底物 PERK、IRE1α 和 p53 的亲和力减弱。因此，UPRs 的改变和 TUSC3 缺乏抑制的 p53-NM23H1/2 途径最终负责增强肺癌的转移潜力。这些发现为 TUSC3 在癌症进展中的未被认识到的作用以及 HRD1 依赖性 ERAD 在癌症转移中的致癌作用提供了机制上的见解。
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